Dementia with Lewy bodies (DLB) may account for 10-15 percent of all cases of dementia in the elderly, yet accurate recognition of the disorder remains a challenge. Diagnostic criteria that include typical DLB features lead to high specificity, but may fail to identify up to 50% of cases later diagnosed at autopsy. Advances in brain volumetry, which have shown promise in initial analysis of data from the Alzheimer's Disease (AD) Neuroimaging Inititative, and diffusion tensor imaging (DTI) may be used to quantify changes in brain atrophy and connectivity resulting from DLB, AD, and healthy aging. The primary goal of the proposed research is to identify brain structural changes that best differentiates these categories and to further examine the bases of such changes using magnetic resonance (MR) microscopy. To achieve this goal, four interrelated experiments are proposed. 1) Quantitative structural imaging will be used to identify the cross- sectional regional volumetric differences that best differentiate DLB, AD and healthy aging. 2) Probabilistic- atlas-based analyses will be used to identify the cross-sectional regional connectivity differences that best differentiate DLB, AD and healthy aging. 3) Assessment of within-subject change in regional volumes and connectivity will be used to identify differences in regional atrophy rates between DLB, AD and healthy aging. 4) MR microscopy will be used to identify the histopathological bases for such regional differences in MR signal. The proposal is based upon a wealth of data suggesting that structural MR imaging may be used to differentiate DLB from AD and upon preliminary studies showing that high-throughput, multi-region quantitative measures may be used to extend previous findings that used qualitative measures or limited- region volumetric assessment using manual tracing. The projects benefit from a convergence of recognized expertise in the neuropsychological assessment of DLB, in the neuropathological assessment of regional synuclein deposition, and in the application of quantitative structural MR imaging to neurodegenerative disorders, including high-field MR microscopy of post mortem tissue. In sum, results from these proposed experiments should provide important insights into the neuropathological bases of differences in MR measures of regional atrophy and connectivity in DLB, AD and healthy aging. RELEVANCE (See instructions): The proposed experiments will evaluate structural changes in the brain that differentiate DLB, AD, and healthy aging. The findings will improve understanding about the effects of neurodegenerative disease on the brain and the neuropathological bases for regional MR changes observed in DLB and AD relative to healthy aging.